A synthetic analog of double-stranded RNA (poly I:C), various viral and other infectious agents induce interferons and interferons activate NK cells. We find that poly I:C and interferons by inducing NK cells suppress the antibody response; the targets for NK cells are not antibody-producing cells but rather accessory cells which have interacted with antigen and are required by the antibody-producing cells (Science 22, 581, 1983). Recently, we have found that poly I:C also suppresses profoundly the challenge delayed type hypersensitivity response to xenogeneic and allogeneic antigens. Furthermore, isolated NK cells suppress the mixed lymphocyte reaction (MLR) which is an assay of T cell proliferation to alloantigens in vitro. Other investigations have shown that both the antibody and MLR responses require the same accessory cell, the dendritic cell, which interacts or combines with antigen. Thus, the inference is that poly I:C and interferons suppress both antibody and delayed type hypersensitivity responses by suppressing or eliminating the accessory cell (dendritic cell?)-antigen combination. In the proposed research, we will determine the effect of poly I:C on both the induction and challenge delayed type hypersensitivity responses to establish whether the effect is indeed mediated by NK cells and, if so, whether responding T cells or accessory cells (dendritic cells?) which have interacted with antigen are the target for NK cells. Finally, if anergy is produced by NK cells, then experiments will be designed to detemrine if anergy can be reversed by eliminating NK cells and/or restoring accessory (dendritic?) cells. Natural killer (NK) cells are cytotoxic for various virally infected and malignantly-transformed cells; thus, NK cells are generally considered a potential line of defense. However, if NK cells also suppress delayed type hypersensitivity, then NK cells may have contrary or paradoxical effects on tumors or viral infections; i.e. NK cells on the one hand may be beneficial because of direct cytotoxicity for tumors or virally infected cells but on the other hand be deleterious because they have the potential for abrogating specific T cell mediated immunity. The proposed research will determine whether indeed NK cells have this latter effect and, if so, whether the deleterious effect of NK cells can be prevented or reversed.